1. health and fitness
2. disease

C H A P T E R 7 Patterns of
Inheritance
Family Studies
If we wish to investigate whether a particular trait or disorder in humans is genetic and hereditary, we usually have
to rely either on observation of the way in which it is transmitted from one generation to another, or on study of its
frequency among relatives.
An important reason for studying the pattern of inheritance of disorders within families is to enable advice to be
given to members of a family regarding the likelihood of
their developing it or passing it on to their children (i.e.,
genetic counseling; see Chapter 17). Taking a family history
can, in itself, provide a diagnosis. For example, a child could
come to the attention of a doctor with a fracture after a
seemingly trivial injury. A family history of relatives with a
similar tendency to fracture and blue sclerae would suggest
the diagnosis of osteogenesis imperfecta. In the absence of
a positive family history, other diagnoses would have to be
considered.
Pedigree Drawing and Terminology
A family tree is a shorthand system of recording the pertinent information about a family. It usually begins with the
person through whom the family came to the attention of
the investigator. This person is referred to as the index case,
proband, or propositus; or, if female, the proposita. The
position of the proband in the family tree is indicated by an
arrow. Information about the health of the rest of the family
is obtained by asking direct questions about brothers, sisters,
parents, and maternal and paternal relatives, with the relevant information about the sex of the individual, affection
status, and relationship to other individuals being carefully
recorded in the pedigree chart (Figure 7.1). Attention to
detail can be crucial because patients do not always appreciate the important difference between siblings and halfsiblings, or might overlook the fact, for example, that the
child of a brother who is at risk of Huntington disease is
actually a step-child and not a biological relative.
Mendelian Inheritance
More than 16,000 traits or disorders in humans exhibit
single gene unifactorial or mendelian inheritance. However,
characteristics such as height, and many common familial
disorders, such as diabetes or hypertension, do not usually
follow a simple pattern of mendelian inheritance (see
Chapter 9).
That the fundamental aspects of heredity should
have turned out to be so extraordinarily simple
supports us in the hope that nature may, after all,
be entirely approachable.
THOMAS MORGAN (1919)
A trait or disorder that is determined by a gene on an
autosome is said to show autosomal inheritance, whereas a
trait or disorder determined by a gene on one of the sex
chromosomes is said to show sex-linked inheritance.
Autosomal Dominant Inheritance
An autosomal dominant trait is one that manifests in the
heterozygous state, that is, in a person possessing both an
abnormal or mutant allele and the normal allele. It is often
possible to trace a dominantly inherited trait or disorder
through many generations of a family (Figure 7.2). In South
Africa the vast majority of cases of porphyria variegata can
be traced back to one couple in the late seventeenth century.
This is a metabolic disorder characterized by skin blistering
as a result of increased sensitivity to sunlight (Figure 7.3),
and the excretion of urine that becomes ‘port wine’ colored
on standing as a result of the presence of porphyrins
(p. 179). This pattern of inheritance is sometimes referred
to as ‘vertical’ transmission and is confirmed when male–
male (i.e., father to son) transmission is observed.
Genetic Risks
Each gamete from an individual with a dominant trait or
disorder will contain either the normal allele or the mutant
allele. If we represent the dominant mutant allele as ‘D’ and
the normal allele as ‘d’, then the possible combinations of
the gametes is seen in Figure 7.4. Any child born to a person
affected with a dominant trait or disorder has a 1 in 2 (50%)
chance of inheriting it and being similarly affected. These
diagrams are often used in the genetic clinic to explain
segregation to patients and are more user-friendly than a
Punnett square (see Figs. 1.3 and 8.1).
Pleiotropy
Autosomal dominant traits may involve only one organ or
part of the body, for example the eye in congenital cataracts.
It is common, however, for autosomal dominant disorders
to manifest in different systems of the body in a variety of
109
110
Patterns of Inheritance
Individuals
Normal
(male, female, unknown sex)
Pregnancy
(LMP or gestation)
P
P
P
LMP
01/06/97
20 wk
Affected individual
Proband
With >2 conditions
P
Multiple individuals
(number known)
5
5
5
Multiple individuals
(number unknown)
n
n
n
P
Consultand
Spontaneous
abortion Male Female
Deceased individual
Affected spontaneous
abortion Male Female
Stillbirth
(gestation)
Termination
of pregnancy
SB
28 wk
Relationships
P
Male Female
Twins
Mating
MZ
DZ
Zygosity
unknown
?
Relationship no
longer exists
No children
Consanguineous
mating
Azoospermia
Infertility
(reason)
Biological parents
known
Adoption in
Adoption out
?
Biological parents
unknown
Assisted reproductive scenarios
D
Sperm donation
Surrogate mother
S
P
P
Ovum donation
D
P
Surrogate ovum donation
D
P
FIGURE 7.1 Symbols used to represent individuals and relationships in family trees.
Patterns of Inheritance
I
II
III
IV
Affected
FIGURE 7.2 Family tree of an autosomal dominant trait. Note
the presence of male-to-male transmission.
111
ways. This is pleiotropy—a single gene that may give rise to
two or more apparently unrelated effects. In tuberous
sclerosis affected individuals can present with a range of
problems including learning difficulties, epilepsy, a facial
rash known as adenoma sebaceum (histologically composed
of blood vessels and fibrous tissue known as angiokeratoma)
or subungual fibromas (Figure 7.5); some affected individuals have all features, whereas others may have almost none.
Some discoveries are challenging our conceptual understanding of the term pleiotropy on account of the remarkably diverse syndromes that can result from different
mutations in the same gene—for example, the LMNA gene
(which encodes lamin A/C) and the X-linked filamin A
FIGURE 7.3 Blistering skin lesions on the hand in porphyria
variegata.
Affected parent
Normal parent
D d
d d
A
D d
d d
D d
d d
Affected
Normal
Affected
Normal
FIGURE 7.4 Segregation of alleles in autosomal dominant inheritance. D represents the mutated allele, whereas d represents the
normal allele.
B
FIGURE 7.5 The facial rash (A) of angiokeratoma (adenoma
sebaceum) in a male with tuberous sclerosis, and a typical subungual fibroma of the nail bed (B).
112
Patterns of Inheritance
FIGURE 7.6 Dunnigan-type familial partial lipodystrophy due to
a mutation in the lamin A/C gene. The patient lacks adipose
tissue, especially in the distal limbs. A wide variety of clinical
phenotypes is associated with mutations in this one gene.
no abnormal clinical features, representing so-called reduced
penetrance or what is commonly referred to in lay terms as
‘skipping a generation’. Reduced penetrance is thought to
be the result of the modifying effects of other genes, as well
as interaction of the gene with environmental factors. An
individual who has no features of a disorder despite being
heterozygous for a particular gene mutation is said to represent non-penetrance.
Reduced penetrance and variable expressivity, together
with the pleiotropic effects of a mutant allele, all need to
be taken into account when trying to interpret family
history information for disorders that follow autosomal
dominant inheritance. A good example of a very variable
condition for which non-penetrance is frequently seen is
Treacher-Collins syndrome. In its most obvious manifestation the facial features are unmistakable (Figure 7.7).
However, the mother of the child illustrated is also known
to harbor the gene (TCOF1) mutation as she has a number
of close relatives with the same condition.
(FLNA) gene. Mutations in LMNA may cause EmeryDreifuss muscular dystrophy, a form of limb girdle muscular
dystrophy, a form of Charcot-Marie-Tooth disease (p. 305),
dilated cardiomyopathy (p. 296) with conduction abnormality, Dunnigan-type familial partial lipodystrophy (Figure
7.6), mandibuloacral dysplasia, and a very rare condition
that has always been a great curiosity—Hutchinson-Gilford
progeria. These are due to heterozygous mutations, with
the exception of the Charcot-Marie-Tooth disease and
mandibuloacral dysplasia, which are recessive—affected
individuals are therefore homozygous for LMNA mutations.
Sometimes an individual with a mutation is entirely normal.
Mutations in the filamin A gene have been implicated
in the distinct, though overlapping, X-linked dominant dysmorphic conditions oto-palato-digital syndrome, MelnickNeedles syndrome and frontometaphyseal dysplasia.
However, it could not have been foreseen that a form of
X-linked dominant epilepsy in women, called periventricular nodular heterotopia, is also due to mutations in this gene.
Variable Expressivity
The clinical features in autosomal dominant disorders can
show striking variation from person to person, even in the
same family. This difference between individuals is referred
to as variable expressivity. In autosomal dominant polycystic kidney disease, for example, some affected individuals
develop renal failure in early adulthood whereas others have
just a few renal cysts that do not affect renal function
significantly.
Reduced Penetrance
In some individuals heterozygous for gene mutations giving
rise to certain autosomal dominant disorders, there may be
FIGURE 7.7 The baby in this picture has Treacher-Collins syndrome, resulting from a mutation in TCOF1. The mandible is
small, the palpebral fissures slant downward, there is usually a
defect (coloboma) of the lower eyelid, the ears may show microtia, and hearing impairment is common. The condition follows
autosomal dominant inheritance but is very variable—the baby’s
mother also has the mutation but she shows no obvious signs
of the condition.
New Mutations
In autosomal dominant disorders an affected person usually
has an affected parent. However, this is not always the case
and it is not unusual for a trait to appear in an individual
when there is no family history of the disorder. A striking
example is achondroplasia, a form of short-limbed dwarfism
(pp. 93–94), in which the parents usually have normal
stature. The sudden unexpected appearance of a condition
arising as a result of a mistake occurring in the transmission
of a gene is called a new mutation. The dominant mode of
inheritance of achondroplasia could be confirmed only by
the observation that the offspring of persons with achondroplasia had a 50% chance of having achondroplasia. In less
dramatic conditions other explanations for the ‘sudden’
appearance of a disorder must be considered. This includes
non-penetrance and variable expression, as mentioned in
the previous section. However, the astute clinician also
needs to be aware that the family relationships may not be
as stated—i.e., there may be undisclosed non-paternity
(p. 342) (or, occasionally, non-maternity).
New dominant mutations, in certain instances, have been
associated with an increased age of the father. Traditionally,
this is believed to be a consequence of the large number of
mitotic divisions that male gamete stem cells undergo
during a man’s reproductive lifetime (p. 41). However, this
may well be a simplistic view. In relation to mutations in
FGFR2 (craniosynostosis syndromes), ground-breaking
work by Wilkie’s group in Oxford demonstrated that causative gain-of-function mutations confer a selective advantage to spermatogonial stem cells, so that mutated cell lines
accumulate in the testis.
Co-Dominance
Co-dominance is the term used for two allelic traits that
are both expressed in the heterozygous state. In persons
with blood group AB it is possible to demonstrate both
A and B blood group substances on the red blood cells,
so the A and B blood groups are therefore co-dominant
(p. 205).
Homozygosity for Autosomal Dominant Traits
The rarity of most autosomal dominant disorders and diseases means that they usually occur only in the heterozygous state. There are, however, a few reports of children
born to couples where both parents are heterozygous
for a dominantly inherited disorder. Offspring of such
couples are, therefore, at risk of being homozygous. In some
instances, affected individuals appear either to be more
severely affected, as has been reported with achondroplasia,
or to have an earlier age of onset, as in familial hypercholesterolemia (p. 175). The heterozygote with a phenotype
intermediate between the homozygotes for the normal and
mutant alleles is consistent with a haploinsufficiency lossof-function mutation (p. 26).
Conversely, with other dominantly inherited disorders,
homozygous individuals are not more severely affected than
Patterns of Inheritance
113
I
II
III
IV
Affected
Consanguineous mating
FIGURE 7.8 Family tree of an autosomal recessive trait.
heterozygotes—e.g., Huntington disease (p. 293) and myotonic dystrophy (p. 295).
Autosomal Recessive Inheritance
Recessive traits and disorders are manifest only when the
mutant allele is present in a double dose (i.e., homozygosity). Individuals heterozygous for such mutant alleles show
no features of the disorder and are perfectly healthy; they
are described as carriers. The family tree for recessive traits
(Figure 7.8) differs markedly from that seen in autosomal
dominant traits. It is not possible to trace an autosomal
recessive trait or disorder through the family, as all the
affected individuals in a family are usually in a single sibship
(i.e., brothers and sisters). This is sometimes referred to as
‘horizontal’ transmission, but this is an inappropriate and
misleading term.
Consanguinity
Enquiry into the family history of individuals affected with
rare recessive traits or disorders might reveal that their
parents are related (i.e., consanguineous). The rarer a
recessive trait or disorder, the greater the frequency of
consanguinity among the parents of affected individuals. In
cystic fibrosis, the most common ‘serious’ autosomal recessive disorder in western Europeans (p. 1), the frequency
of parental consanguinity is only slightly greater than that
seen in the general population. By contrast, in alkaptonuria,
one of the original inborn errors of metabolism (p. 171),
which is an exceedingly rare recessive disorder, Bateson and
Garrod, in their original description of the disorder, observed
that one-quarter or more of the parents were first cousins.
They reasoned that rare alleles for disorders such as alkaptonuria are more likely to ‘meet up’ in the offspring of
cousins than in the offspring of parents who are unrelated.
In large inbred kindreds an autosomal recessive condition
may be present in more than one branch of the family.
Genetic Risks
If we represent the normal dominant allele as ‘R’ and the
recessive mutant allele as ‘r’, then each parental gamete
carries either the mutant or the normal allele (Figure 7.9).
The various possible combinations of gametes mean that the
offspring of two heterozygotes have a 1 in 4 (25%) chance
of being homozygous affected, a 1 in 2 (50%) chance of
114
Patterns of Inheritance
Carrier father
Carrier mother
R r
R r
R R
R r
R r
Normal
Carrier
Carrier
r
r
Affected
FIGURE 7.9 Segregation of alleles in autosomal recessive inheritance. R represents the normal allele, r the mutated allele.
often choose to have children with another deaf person.
It would be expected that, if two deaf persons were homozygous for the same recessive gene, all of their children
would be similarly affected. Families have been described
in which all the children born to parents who are deaf due
to autosomal recessive genes have had perfectly normal
hearing because they are double heterozygotes. The explanation is that the parents were homozygous for mutant
alleles at different loci (i.e., different genes can cause autosomal recessive sensorineural deafness). In fact, over the
past 10 to 15 years, approximately 30 genes and a further
50 loci have been shown to be involved. A very similar story
applies to autosomal recessive retinitis pigmentosa, and to
a lesser extent primary autosomal recessive microcephaly.
Disorders with the same phenotype from different
genetic loci are known as genocopies, whereas, when the
same phenotype results from environmental causes it is
known as a phenocopy.
Mutational Heterogeneity
If an individual who is homozygous for an autosomal recessive disorder has children with a carrier of the same disorder, their offspring have a 1 in 2 (50%) chance of being
affected. Such a pedigree is said to exhibit pseudodominance (Figure 7.10).
Heterogeneity can also occur at the allelic level. In the
majority of single-gene disorders (e.g., β-thalassemia) a
large number of different mutations have been identified as
being responsible (p. 160). There are individuals who have
two different mutations at the same locus and are known
as compound heterozygotes, constituting what is known as
allelic or mutational heterogeneity. Most individuals
affected with an autosomal recessive disorder are probably
compound heterozygotes rather than true homozygotes,
unless their parents are related, when they are likely to be
homozygous for the same mutation by descent, having
inherited the same mutation from a common ancestor.
Locus Heterogeneity
Sex-Linked Inheritance
A disorder inherited in the same manner can be due to
mutations in more than one gene, or what is known as locus
heterogeneity. For example, it is recognized that sensorineural hearing impairment/deafness most commonly shows
autosomal recessive inheritance. Deaf persons, by virtue of
their schooling and involvement in the deaf community,
Sex-linked inheritance refers to the pattern of inheritance
shown by genes that are located on either of the sex chromosomes. Genes carried on the X chromosome are referred
to as being X-linked, and those carried on the Y chromosome are referred to as exhibiting Y-linked or holandric
inheritance.
being heterozygous unaffected, and a 1 in 4 (25%) chance
of being homozygous unaffected.
Pseudodominance
X-Linked Recessive Inheritance
I
1
2
1
2
II
Homozygous
Heterozygous
FIGURE 7.10 A pedigree with a woman (I2) homozygous for an
autosomal recessive disorder whose husband is heterozygous for
the same disorder. They have a homozygous affected daughter
so that the pedigree shows pseudodominant inheritance.
An X-linked recessive trait is one determined by a gene
carried on the X chromosome and usually manifests only in
males. A male with a mutant allele on his single X chromosome is said to be hemizygous for that allele. Diseases
inherited in an X-linked manner are transmitted by healthy
heterozygous female carriers to affected males, as well as
by affected males to their obligate carrier daughters, with
a consequent risk to male grandchildren through these
daughters (Figure 7.11). This type of pedigree is sometimes
said to show ‘diagonal’ or a ‘knight’s move’ pattern of
transmission.
The mode of inheritance whereby only males are affected
by a disease that is transmitted by normal females was
appreciated by the Jews nearly 2000 years ago. They
excused from circumcision the sons of all the sisters of a
Patterns of Inheritance
I
Normal father
Carrier mother
X Y
X Xr
115
II
III
IV
Affected
Carrier
FIGURE 7.11 Family tree of an X-linked recessive trait in which
affected males reproduce.
mother who had sons with the ‘bleeding disease’, in other
words, hemophilia (p. 309). The sons of the father’s siblings
were not excused. Queen Victoria was a carrier of hemophilia, and her carrier daughters, who were perfectly healthy,
introduced the gene into the Russian and Spanish royal
families. Fortunately for the British royal family, Queen
Victoria’s son, Edward VII, did not inherit the gene and so
could not transmit it to his descendants.
X X
X Y
X Xr
Xr Y
Normal
daughter
Normal
son
Carrier
daughter
Affected
son
FIGURE 7.13 Segregation of alleles in X-linked recessive inheritance, relating to the offspring of a carrier female. r represents
the mutated allele.
Genetic Risks
A male transmits his X chromosome to each of his daughters and his Y chromosome to each of his sons. If a male
affected with hemophilia has children with a normal female,
then all of his daughters will be obligate carriers but none
of his sons will be affected (Figure 7.12). A male cannot
transmit an X-linked trait to his son, with the very rare
exception of uniparental heterodisomy (p. 121).
Affected father
Normal mother
Xr Y
X X
For a carrier female of an X-linked recessive disorder
having children with a normal male, each son has a 1 in 2
(50%) chance of being affected and each daughter has a 1
in 2 (50%) chance of being a carrier (Figure 7.13).
Some X-linked disorders are not compatible with survival to reproductive age and are not, therefore, transmitted
by affected males. Duchenne muscular dystrophy is the
commonest muscular dystrophy and is a severe disease
(p. 307). The first sign is delayed walking followed by a
waddling gait, difficulty in climbing stairs unaided, and a
tendency to fall easily. By about the age of 10 years affected
boys usually need to use a wheelchair. The muscle weakness
progresses gradually and affected males ultimately become
confined to bed and often die in their late teenage years or
early 20s (Figure 7.14). Because affected boys do not
usually survive to reproduce, the disease is transmitted by
healthy female carriers (Figure 7.15), or may arise as a new
mutation.
Variable Expression in Heterozygous Females
X Xr
X Y
X Xr
X Y
Carrier
daughter
Normal
son
Carrier
daughter
Normal
son
FIGURE 7.12 Segregation of alleles in X-linked recessive inheritance, relating to the offspring of an affected male. r represents
the mutated allele.
In humans, several X-linked disorders are known in which
heterozygous females have a mosaic phenotype with a
mixture of features of the normal and mutant alleles. In
X-linked ocular albinism, the iris and ocular fundus of
affected males lack pigment. Careful examination of the
ocular fundus in females heterozygous for ocular albinism
reveals a mosaic pattern of pigmentation (see Figure 6.25,
p. 104). This mosaic pattern of involvement can be explained
by the random process of X-inactivation (p. 103). In the
pigmented areas, the normal gene is on the active X chromosome, whereas in the depigmented areas the mutant
allele is on the active X chromosome.
116
Patterns of Inheritance
green. About 8% of males are red-green color blind and,
although it is unusual, because of the high frequency of this
allele in the population about 1 in 150 women are red-green
color-blind by virtue of both parents having the allele on the
X chromosome. Therefore, a female can be affected with
an X-linked recessive disorder as a result of homozygosity
for an X-linked allele, although the rarity of most X-linked
conditions means that the phenomenon is uncommon. A
female could also be homozygous if her father was affected
and her mother was normal, but a new mutation occurred
on the X chromosome transmitted to the daughter; alternatively, it could happen if her mother was a carrier and her
father was normal, but a new mutation occurred on the X
chromosome he transmitted to his daughter—but these
scenarios are rare.
FIGURE 7.14 Boy with Duchenne muscular dystrophy; note the
enlarged calves and wasting of the thigh muscles.
Females Affected with X-Linked Recessive Disorders
Occasionally a woman might manifest features of an
X-linked recessive trait. There are several explanations for
how this can happen.
Homozygosity for X-Linked Recessive Disorders. A com­­
mon X-linked recessive trait is red–green color blindness
—the inability to distinguish between the colors red and
I
II
III
IV
Affected
Carrier
FIGURE 7.15 Family tree of Duchenne muscular dystrophy with
the disorder being transmitted by carrier females and affecting
males, who do not survive to transmit the disorder.
Skewed X-Inactivation. The process of X-inactivation
(p. 103) usually occurs randomly, there being an equal
chance of either of the two X chromosomes in a hetero­
zygous female being inactivated in any one cell. After
X-inactivation in embryogenesis, therefore, in roughly half
the cells one of the X chromosomes is active, whereas in
the other half it is the other X chromosome that is active.
Sometimes this process is not random, allowing for the
possibility that the active X chromosome in most of the
cells of a heterozygous female carrier is the one bearing
the mutant allele. If this happens, a carrier female would
exhibit some of the symptoms and signs of the disease and
be a so-called manifesting heterozygote or carrier. This has
been reported in a number of X-linked disorders, including
Duchenne muscular dys­trophy and hemophilia A (pp. 307,
309). In addition, there are reports of several X-linked
disorders in which there are a number of manifesting car­
riers in the same family, con­sistent with the coincidental
inheritance of an abnormality of X-inactivation (p. 204).
Numerical X-Chromosome Abnormalities. A female could
manifest an X-linked recessive disorder by being a carrier
of an X-linked recessive mutation and having only a single
X chromosome (i.e., Turner syndrome, see p. 207). Women
with Turner syndrome and hemophilia A or Duchenne muscular dystrophy have been reported occasionally.
X-Autosome Translocations. Females with a translocation
involving one of the X chromosomes and an autosome can
be affected with an X-linked recessive disorder. If the
breakpoint of the translocation disrupts a gene on the
X chromosome, then a female can be affected. This is
because the X chromosome involved in the translocation
survives preferentially so as to maintain functional disomy
of the autosomal genes (Figure 7.16). The observation of
females affected with Duchenne muscular dystrophy with
X-autosome translocations involving the same region of the
short arm of the X chromosome helped to map the
Duchenne muscular dystrophy gene (p. 307). This type of
observation has been vital in the positional cloning of a
number of genes in humans (p. 75).
Patterns of Inheritance
disorder there is an excess of affected females and direct
male-to-male transmission cannot occur.
An example of an X-linked dominant trait is X-linked
hypophosphatemia, also known as vitamin D–resistant
rickets. Rickets can be due to a dietary deficiency of vitamin
D, but in vitamin D–resistant rickets the disorder occurs
even when there is an adequate dietary intake of vitamin
D. In the X-linked dominant form of vitamin D–resistant
rickets, both males and females are affected with short
stature due to short and often bowed long bones, although
the females usually have less severe skeletal changes than
the males. The X-linked form of Charcot-Marie-Tooth
disease (hereditary motor and sensory neuropathy) is
another example.
A mosaic pattern of involvement can be demonstrated
in females heterozygous for some X-linked dominant disorders. An example is the mosaic pattern of abnormal pigmentation of the skin that follows developmental lines seen
in females heterozygous for the X-linked dominant disorder
incontinentia pigmenti (Figure 7.18). This is also an example
of a disorder that is usually lethal for male embryos that
inherit the mutated allele. Others include the neurological
conditions Rett syndrome and periventricular nodular
heterotopia.
Break
points
Xp2 1
X chromosomes
Autosomes
A
B
50%
50%
A
B
Normal
X chromosome
inactivated
I
N
A
C
T
I
V
A
T
I
O
N
117
Y-Linked Inheritance
A
B
Derivative
X chromosome
inactivated
Cells survive with
Cell death due to
breakpoint at Xp21 leading
inactivation of
to development of DMD autosome segment
FIGURE 7.16 Generation of an X-autosome translocation with
breakpoint in a female and how this results in the development
of Duchenne muscular dystrophy.
Y-linked or holandric inheritance implies that only males
are affected. An affected male transmits Y-linked traits to
all of his sons but to none of his daughters. In the past it
has been suggested that bizarre-sounding conditions such
as porcupine skin, hairy ears and webbed toes are Y-linked
traits. With the possible exception of hairy ears, these
claims of holandric inheritance have not stood up to more
careful study. Evidence clearly indicates, however, that the
H-Y histocompatibility antigen (p. 200) and genes involved
in spermatogenesis are carried on the Y chromosome and,
therefore, manifest holandric inheritance. The latter, if
deleted, leads to infertility from azoospermia (absence of
the sperm in semen) in males. The recent advent of techniques of assisted reproduction, particularly the technique
of intracytoplasmic sperm injection (ICSI), means that, if
a pregnancy with a male conceptus results after the use of
this technique, the child will also necessarily be infertile.
X-Linked Dominant Inheritance
Although uncommon, there are disorders that are manifest
in the heterozygous female as well as in the male who has
the mutant allele on his single X chromosome. This is
known as X-linked dominant inheritance (Figure 7.17).
X-linked dominant inheritance superficially resembles that
of an autosomal dominant trait because both the daughters
and sons of an affected female have a 1 in 2 (50%) chance
of being affected. There is, however, an important difference. With an X-linked dominant trait, an affected male
transmits the trait to all his daughters but to none of his
sons. Therefore, in families with an X-linked dominant
I
II
III
IV
Affected
FIGURE 7.17 Family tree of an X-linked dominant trait.
118
Patterns of Inheritance
somal dominant traits, males being predominantly affected
in both cases. The influence of sex in these two examples
is probably through the effect of male hormones. Gout,
for example, is very rare in women before the menopause
but the frequency increases in later life. Baldness does not
occur in males who have been castrated. In hemochromatosis (p. 244), the most common autosomal recessive disorder in Western society, homozygous females are much
less likely than homozygous males to develop iron overload
and associated symptoms; the explanation usually given is
that women have a form of natural blood loss through
menstruation.
Sex Limitation
Sex limitation refers to the appearance of certain features
only in individuals of a particular sex. Examples include
virilization of female infants affected with the autosomal
recessive endocrine disorder, congenital adrenal hyperplasia
(p. 174).
Establishing the Mode of Inheritance
of a Genetic Disorder
FIGURE 7.18 Mosaic pattern of skin pigmentation in a female
with the X-linked dominant disorder, incontinentia pigmenti.
The patient has a mutation in a gene on one of her X chromosomes; the pigmented areas indicate tissue in which the normal
X chromosome has been inactivated. This developmental
pattern follows Blaschko’s lines (see Chapter 18, p. 276).
Partial Sex-Linkage
Partial sex-linkage has been used in the past to account for
certain disorders that appear to exhibit autosomal dominant
inheritance in some families and X-linked inheritance in
others. This is now known to be likely to be because of
genes carried on that portion of the X chromosome sharing
homology with the Y chromosome, and which escapes
X-inactivation. During meiosis, pairing occurs between the
homologous distal parts of the short arms of the X and
Y chromosomes, the so-called pseudoautosomal region. As
a result of a cross-over, a gene could be transferred from the
X to the Y chromosome, or vice versa, allowing the possibility of male-to-male transmission. The latter instances would
be consistent with autosomal dominant inheritance. A rare
skeletal dysplasia, Leri-Weil dyschondrosteosis, in which
affected individuals have short stature and a characteristic
wrist deformity (Madelung deformity), has been reported
to show both autosomal dominant and X-linked inheritance.
The disorder has been shown to be due to deletions of, or
mutations in, the short stature homeobox (SHOX) gene,
which is located in the pseudoautosomal region.
Sex Influence
Some autosomal traits are expressed more frequently in
one sex than in another—so-called sex influence. Gout and
presenile baldness are examples of sex-influenced auto­
In experimental animals it is possible to arrange specific
types of mating to establish the mode of inheritance of a
trait or disorder. In humans, when a disorder is newly recognized, the geneticist approaches the problem indirectly
by fitting likely models of inheritance to the observed
outcome in the offspring. Certain features are necessary to
support a particular mode of inheritance. Formally establishing the mode of inheritance is not usually possible with
a single family and normally requires study of a number of
families (Box 7.1).
Box 7.1 Features that Support the Single-Gene
or Mendelian Patterns of Inheritance
Autosomal Dominant
Males and females affected in equal proportions
Affected individuals in multiple generations
Transmission by individuals of both sexes (i.e., male to male,
female to female, male to female, and female to male)
Autosomal Recessives
Males and females affected in equal proportions
Affected individuals usually in only a single generation
Parents can be related (i.e., consanguineous)
X-Linked Recessive
Only males usually affected
Transmitted through unaffected females
Males cannot transmit the disorder to their sons (i.e., no
male-to-male transmission)
X-Linked Dominant
Males and females affected but often an excess of females
Females less severely affected than males
Affected males can transmit the disorder to their daughters but
not to sons
Y-Linked Inheritance
Affected males only
Affected males must transmit it to their sons
Patterns of Inheritance
119
Autosomal Dominant Inheritance
Multiple Alleles and Complex Traits
To determine whether a trait or disorder is inherited in an
autosomal dominant manner, there are three specific features that need to be observed. First, it should affect
both males and females in equal proportions. Second, it
is transmitted from one generation to the next. Third,
all forms of transmission between the sexes are observed
(i.e., male to male, female to female, male to female,
and female to male). Male-to-male transmission excludes
the possibility of the gene being on the X chromosome.
In the case of sporadically occurring disorders, increased
paternal age may suggest a new autosomal dominant
mutation.
There are three main features necessary to establish X-linked
recessive inheritance. First, the trait or disorder should
affect males almost exclusively. Second, X-linked recessive
disorders are transmitted through unaffected carrier females
to their sons. Affected males, if they survive to reproduce,
can have affected grandsons through their daughters who
are obligate carriers. Thirdly, male-to-male transmission is
not observed (i.e., affected males cannot transmit the disorder to their sons).
So far, each of the traits we have considered has involved
only two alleles, the normal, and the mutant. However,
some traits and diseases are neither monogenic nor polygenic. Some genes have more than two allelic forms (i.e.,
multiple alleles). Multiple alleles are the result of a normal
gene having mutated to produce various different alleles,
some of which can be dominant and others recessive to the
normal allele. In the case of the ABO blood group system
(p. 205), there are at least four alleles (A1, A2, B, and O).
An individual can possess any two of these alleles, which
may be the same or different (AO, A2B, OO, and so on).
Alleles are carried on homologous chromosomes and therefore a person transmits only one allele for a certain trait to
any particular offspring. For example, a person with the
genotype AB will transmit to any particular offspring either
the A allele or the B allele, but never both or neither (Table
7.1). This relates only to genes located on the autosomes
and does not apply to alleles on the X chromosome; in this
instance a woman would have two alleles, either of which
could be transmitted to offspring, whereas a man only has
one allele to transmit.
The dramatic advances in genome wide scanning using
multiple DNA probes has made it possible to begin investigating so-called complex traits (i.e., conditions that are
usually much more common than mendelian disorders and
likely to be due to the interaction of more than one gene).
The effects may be additive, one may be rate limiting over
the action of another, or one may enhance or multiply the
effect of another; this is considered in more detail in
Chapter 15. The possibility of a small number of gene loci
being implicated in some disorders has given rise to the
concept of oligogenic inheritance, examples of which
include the following.
X-Linked Dominant Inheritance
Digenic Inheritance
There are three features necessary to establish X-linked
dominant inheritance. First, males and females are affected
but affected females are more frequent than affected males.
Second, females are usually less severely affected than
males. Third, although affected females can transmit the
disorder to both male and female offspring, affected males
can transmit the disorder only to their daughters (except
in partial sex-linkage; see p. 118), all of whom will be
affected. In the case of X-linked dominant disorders that
are almost invariably lethal in male embryos (e.g., incontinentia pigmenti; see pp. 117–118), only females will be
affected and families may show an excess of females over
males as well as a number of miscarriages that are the
affected male pregnancies.
This refers to the situation where a disorder has been shown
to be due to the additive effects of heterozygous mutations
at two different gene loci, a concept referred to as digenic
inheritance. This is seen in certain transgenic mice. Mice
Autosomal Recessive Inheritance
There are three features that suggest the possibility of
autosomal recessive inheritance. First, the disorder affects
males and females in equal proportions. Second, it usually
affects only individuals in one generation in a single sibship
(i.e., brothers and sisters) and does not occur in previous
and subsequent generations. Third, consanguinity in the
parents provides further support for autosomal recessive
inheritance.
X-Linked Recessive Inheritance
Y-Linked Inheritance
There are two features necessary to establish a Y-linked
pattern of inheritance. First, it affects only males. Second,
affected males must transmit the disorder to their sons
(e.g., male infertility by ICSI) (p. 117).
Table 7.1 Possible Genotypes, Phenotypes, and
Gametes Formed from the Four Alleles
A1, A2, B, and O at the ABO Locus
Genotype
Phenotype
Gametes
A1A1
A2A2
BB
OO
A1A2
A1B
A1O
A2B
A2O
BO
A1
A2
B
O
A1
A1B
A1
A2B
A2
B
A1
A2
B
O
A1 or A2
A1 or B
A1 or O
A2 or B
A2 or O
B or O
120
Patterns of Inheritance
that are homozygotes for rv (rib-vertebrae) or Dll1
(Delta–like-1) manifest abnormal phenotypes, whereas
their respective heterozygotes are normal. However, mice
that are double heterozygotes for rv and Dll1 show vertebral defects. In humans, one form of retinitis pigmentosa,
a disorder of progressive visual impairment, is caused by
double heterozygosity for mutations in two unlinked genes,
ROM1 and Peripherin, which both encode proteins present
in photoreceptors. Individuals with only one of these mutations are not affected. In the field of inherited cardiac
arrhythmias and cardiomyopathies (p. 304), it is becoming
clear that some cases of arrhythmogenic right ventricular
dysplasia exhibit digenic inheritance.
Triallelic Inheritance
Bardet–Biedl syndrome is a rare dysmorphic condition
(though relatively more common in some inbred communities) with obesity, polydactyly, renal abnormalities, retinal
pigmentation, and learning disability. Seven different gene
loci have been identified and, until recently, the syndrome
was thought to follow straightforward autosomal recessive
inheritance. However, it is now known that one form
occurs only when an individual who is homozygous for
mutations at one locus is also heterozygous for mutation at
another Bardet-Biedl locus; this is referred to as triallelic
inheritance.
Other patterns of inheritance that are not classically
mendelian are also recognized and explain some unusual
phenomena.
Anticipation
In some autosomal dominant traits or disorders, such as
myotonic dystrophy, the onset of the disease occurs at an
earlier age in the offspring than in the parents, or the disease
occurs with increasing severity in subsequent generations.
This phenomenon is called anticipation. It used to be
believed that this effect was the result of a bias of ascertainment, because of the way in which the families were collected. It was argued that this arose because persons in
whom the disease begins earlier, or is more severe, are more
likely to be ascertained and only those individuals who are
less severely affected tend to have children. In addition, it
was thought that, because the observer is in the same generation as the affected presenting probands, many individuals who at present are unaffected will, by necessity, develop
the disease later in life.
Recent studies, however, have shown that in a number
of disorders, including Huntington disease and myotonic
dystrophy, anticipation is, in fact, a real biological phenomenon occurring as a result of the expansion of unstable
triplet repeat sequences (p. 24). An expansion of the CTG
triplet repeat in the 3′ untranslated end of the myotonic
dystrophy gene, occurring predominantly in maternal
meiosis, appears to be the explanation for the severe neonatal form of myotonic dystrophy that usually only occurs
when the gene is transmitted by the mother (Figure 7.19).
FIGURE 7.19 Newborn baby with severe hypotonia requiring
ventilation as a result of having inherited myotonic dystrophy
from his mother.
Fragile X syndrome (CGG repeats) (p. 278) behaves in a
similar way, with major instability in the expansion occurring during maternal meiosis. A similar expansion—in this
case CAG repeats—in the 5′ end of the Huntington disease
gene (Figure 7.20) in paternal meiosis accounts for the
increased risk of early onset Huntington disease, occasionally in childhood or adolescence, when the gene is transmitted by the father. The inherited spinocerebellar ataxia group
of conditions is another example.
Mosaicism
An individual, or a particular tissue of the body, can consist
of more than one cell type or line, through an error occurring during mitosis at any stage after conception. This is
known as mosaicism (p. 50). Mosaicism of either somatic
tissues or germ cells can account for some instances of
unusual patterns of inheritance or phenotypic features in an
affected individual.
Somatic Mosaicism
The possibility of somatic mosaicism is suggested by the
features of a single-gene disorder being less severe in an
individual than is usual, or by being confined to a particular
part of the body in a segmental distribution; for example,
as occurs occasionally in neurofibromatosis type I (p. 298).
The timing of the mutation event in early development may
determine whether it is transmitted to the next generation
with full expression—this will depend on the mutation
being present in all or some of the gonadal tissue, and hence
germline cells.
Patterns of Inheritance
–
+
FIGURE 7.20 Silver staining of a 5% denaturing gel of the po­
lymerase chain reaction products of the CAG triplet in the 5’
untranslated end of the Huntington disease gene from an
affected male and his wife, showing her to have two similar-sized
repeats in the normal range (20 and 24 copies) and him to
have one normal-sized triplet repeat (18 copies) and an expanded triplet repeat (44 copies). The bands in the left lane are
standard markers to allow sizing of the CAG repeat. (Courtesy
Alan Dodge, Regional DNA Laboratory, St. Mary’s Hospital,
Manchester, UK.)
121
the past decade, with the advent of DNA technology, some
individuals have been shown to have inherited both homologs of a chromosome pair from only one of their parents,
so-called uniparental disomy. If an individual inherits two
copies of the same homolog from one parent, through an
error in meiosis II (p. 41), this is called uniparental isodisomy (Figure 7.21). If, however, the individual inherits the
two different homologs from one parent through an error
in meiosis I (p. 39), this is termed uniparental heterodisomy. In either instance, it is presumed that the conceptus
would originally be trisomic, with early loss of a chromosome leading to the ‘normal’ disomic state. One-third of
such chromosome losses, if they occurred with equal frequency, would result in uniparental disomy. Alternatively,
it is postulated that uniparental disomy could arise as a
result of a gamete from one parent that does not contain
a particular chromosome homolog (i.e., a gamete that is
nullisomic), being ‘rescued’ by fertilization with a gamete
that, through a second separate chance error in meiosis, is
disomic.
Using DNA techniques, uniparental disomy has been
shown to be the cause of a father with hemophilia having
an affected son and of a child with cystic fibrosis being born
to a couple in which only the mother was a carrier (with
proven paternity!). Uniparental paternal disomy for chromosome 15 may be linked to either Prader-Willi or Angelman syndrome, or for chromosome 11 with a proportion of
cases of the overgrowth condition known as the BeckwithWiedemann syndrome (see the following section).
Genomic Imprinting
Gonadal Mosaicism
There have been many reports of families with autosomal
dominant disorders, such as achondroplasia and osteogenesis imperfecta, and X-linked recessive disorders, such as
Duchenne muscular dystrophy and hemophilia, in which
the parents are phenotypically normal, and the results of
investigations or genetic tests have also all been normal, but
in which more than one of their children has been affected.
The most favored explanation for these observations is
gonadal, or germline, mosaicism in one of the parents; that
is, the mutation is present in a proportion of the gonadal or
germline cells. An elegant example of this was provided by
the demonstration of a mutation in the collagen gene
responsible for osteogenesis imperfecta in a proportion of
individual sperm from a clinically normal father who had
two affected infants with different partners. It is important
to keep germline mosaicism in mind when providing
recurrence risks in genetic counseling for apparently
new autosomal dominant and X-linked recessive mutations
(p. 343).
Uniparental Disomy
An individual normally inherits one of a pair of
homologous chromosomes from each parent (p. 39). Over
Genomic imprinting is an epigenetic phenomenon, referred
to in Chapter 6 (p. 103). Epigenetics and genomic imprinting give the lie to Thomas Morgan’s quotation at the start
of this chapter! Although it was originally thought that
genes on homologous chromosomes were expressed equally,
it is now recognized that different clinical features can
result, depending on whether a gene is inherited from the
father or from the mother. This ‘parent of origin’ effect is
referred to as genomic imprinting, and methylation of
DNA is thought to be the main mechanism by which
expression is modified. Methylation is the imprint applied
to certain DNA sequences in their passage through gametogenesis, although only a small proportion of the human
genome is in fact subject to this process. The differential
allele expression (i.e., maternal or paternal) may occur in
all somatic cells, or in specific tissues or stages of development. Thus far, at least 80 human genes are known to be
imprinted and the regions involved are known as differentially methylated regions (DMRs). These DMRs include
imprinting control regions (ICRs) that control gene expression across imprinted domains.
Evidence of genomic imprinting has been observed
in two pairs of well known dysmorphic syndromes:
Prader-Willi and Angelman syndromes (chromosome 15q),
and Beckwith-Wiedemann and Russell-Silver syndromes
122
A
Patterns of Inheritance
Meiosis I
Meiosis I
Meiosis II
Meiosis II
Fertilization
Fertilization
Loss of
chromosome
Loss of
chromosome
Uniparental
isodisomy
B
Uniparental
heterodisomy
FIGURE 7.21 Mechanism of origin of uniparental disomy. A, Uniparental isodisomy occurring through a disomic gamete arising
from non-disjunction in meiosis II fertilizing a monosomic gamete with loss of the chromosome from the parent contributing the
single homolog. B, Uniparental heterodisomy occurring through a disomic gamete arising from non-disjunction in meiosis I fertilizing
a monosomic gamete with loss of the chromosome from the parent contributing the single homolog.
(chromosome 11p). The mechanisms giving rise to these
conditions, although complex, reveal much about imprinting and are therefore now considered in a little detail.
Prader-Willi Syndrome
Prader-Willi syndrome (PWS) (p. 282) occurs in approximately 1 in 20,000 births and is characterized by short
stature, obesity, hypogonadism, and learning difficulty
(Figure 7.22). Approximately 50% to 60% of individuals
with PWS can be shown to have an interstitial deletion of
the proximal portion of the long arm of chromosome 15,
approximately 2 Mb at 15q11-q13, visible by conventional
cytogenetic means, and in a further 15% a submicroscopic
deletion can be demonstrated by fluorescent in-situ hybridization (see p. 34) or molecular means. DNA analysis has
revealed that the chromosome deleted is almost always the
paternally derived homolog. Most of the remaining 25%
to 30% of individuals with PWS, without a chromosome
deletion, have been shown to have maternal uniparental
disomy. Functionally, this is equivalent to a deletion in the
paternally derived chromosome 15.
FIGURE 7.22 Female child with Prader-Willi syndrome.
Patterns of Inheritance
123
Paternal allele
Centromere
Telomere
PWS ICR
UBE3A
Antisense
5'
3'
UBE3A
SNURF/SNRPN
MKRN3
NDN
AS ICR
MAGE-L2
Maternal allele
FIGURE 7.23 Molecular organization (simplified) at 15q11-q13: Prader-Willi syndrome (PWS) and Angelman syndrome (AS). The
imprinting control region (ICR) for this locus has two components. The more telomeric acts as the PWS ICR and contains the promoter of SNURF/SNRPN. SNURF/SNRPN produces several long and complex transcripts, one of which is believed to be an RNA
antisense inhibitor of UBE3A. The more centromeric ICR acts as the AS ICR on UBE3A, which is the only gene whose maternal expression is lost in AS. The AS ICR also inhibits the PWS ICR on the maternal allele. The PWS ICR also acts on the upstream genes MKRN3,
MAGE-L2, and NDN, which are unmethylated () on the paternal allele but methylated (•) on the maternal allele.
It is now known that only the paternally inherited
allele of this critical region of 15q11-q13 is expressed. The
molecular organization of the region is shown in Figure 7.23.
PWS is a multigene disorder and in the normal situation the
small nuclear ribonucleoprotein polypeptide N (SNRPN)
and adjacent genes (MKRN3, etc.) are paternally expressed.
Expression is under the control of a specific ICR. Analysis
of DNA from patients with PWS and various submicro­
scopic deletions enabled the ICR to be mapped to a segment
of about 4 kb, spanning the first exon and promoter of
SNRPN and upstream reading frame (SNURF). The 3′ end
of the ICR is required for expression of the paternally
expressed genes and also the origin of the long SNURF/
SNRPN transcript. The maternally expressed genes are
not differentially methylated but they are silenced on the
paternal allele, probably by an antisense RNA generated
from SNURF/SNRPN. In normal cells, the 5′ end of the
ICR, needed for maternal expression and involved in
Angelman syndrome (see below), is methylated on the
maternal allele.
A
Angelman Syndrome (AS)
Angelman syndrome (p. 282) occurs in about 1 in 15,000
births and is characterized by epilepsy, severe learning difficulties, an unsteady or ataxic gait, and a happy affect
(Figure 7.24). Approximately 70% of individuals with AS
have been shown to have an interstitial deletion of the same
15q11-q13 region as is involved in PWS, but in this case on
the maternally derived homolog. In a further 5% of individuals with AS, the syndrome can be shown to have arisen
through paternal uniparental disomy. Unlike PWS, the features of AS arise through loss of a single gene, UBE3A. In
up to 10% of individuals with AS, mutations have been
identified in UBE3A, one of the ubiquitin genes, which
appears to be preferentially or exclusively expressed from
the maternally derived chromosome 15 in brain. How
mutations in UBE3A lead to the features seen in persons
with AS is not clear, but could involve ubiquitin-mediated
destruction of proteins in the central nervous system in
B
FIGURE 7.24 A, Female child with Angelman syndrome.
B, Adult male with Angelman syndrome.
124
1
Patterns of Inheritance
2
3
4
Beckwith-Wiedemann Syndrome
4.2 kb Maternal band
0.9 kb Paternal band
FIGURE 7.25 Southern blot to detect methylations of SNRPN.
DNA digested with Xba I and Not I was probed with KB17, which
hybridizes to a CpG island within exon a of SNRPN. Patient 1
has Prader-Willi syndrome, patient 2 has Angelman syndrome,
and patients 3 and 4 are unaffected. (Courtesy A. Gardner,
Department of Molecular Genetics, Southmead Hospital, Bristol.)
development, particularly where UBE3A is expressed most
strongly, namely the hippocampus and Purkinje cells of the
cerebellum. UBE3A is under control of the AS ICR (see
Figure 7.23), which was mapped slightly upstream of
SNURF/SNRPN through analysis of patients with AS who
had various different microdeletions.
About 2% of individuals with PWS and approximately
5% of those with AS have abnormalities of the ICR itself;
these patients tend to show the mildest phenotypes. Patients
in this last group, unlike the other three, have a risk of
recurrence. In the case of AS, if the mother carries the same
mutation as the child, the recurrence risk is 50%, but even
if she tests negative for the mutation, there is an appreciable
recurrence risk from gonadal mosaicism.
Rare families have been reported in which a translocation
of the proximal portion of the long arm of chromosome 15
is segregating. Depending on whether the translocation is
transmitted by the father or mother, affected offspring
within the family have had either PWS or AS. In approximately 10% of AS cases the molecular defect is unknown—
but it may well be that some of these alleged cases have a
different, albeit phenotypically similar, diagnosis.
In many genetics service laboratories a simple DNA test
is used to diagnose both PWS and AS, exploiting the differential DNA methylation characteristics at the 15q11q13 locus (Figure 7.25).
Beckwith–Wiedemann syndrome (BWS) is a clinically heterogeneous condition whose main underlying characteristic
is overgrowth. First described in 1963 and 1964, the main
features are macrosomia (prenatal and/or postnatal overgrowth), macroglossia (large tongue), abdominal wall defect
(omphalocele, umbilical hernia, diastasis recti), and neonatal hypoglycemia (Figure 7.26). Hemihyperplasia may be
present, as well as visceromegaly, renal abnormalities, ear
anomalies (anterior earlobe creases, posterior helical pits)
and cleft palate, and there may be embryonal tumors (particularly Wilms tumor).
BWS is, in a way, celebrated in medical genetics because
of the multiple different (and complex) molecular mechanisms that underlie it. Genomic imprinting, somatic mosaicism, and multiple genes are involved, all within a 1 Mb
region at chromosome 11p15 (Figure 7.27). Within this
region lie two independently regulated imprinted domains.
The more telomeric (differentially methylated region 1
[DMR1] under control of ICR1) contains paternally
expressed IGF2 (insulin growth factor 2) and maternally
expressed H19. The more centromeric imprinted domain
(DMR2, under control of ICR2) contains the maternally
expressed KCNQ1 (previously known as KvLQT1) and
CDKN1C genes, and the paternally expressed antisense
transcript KCNQ1OT1, the promoter for which is located
within the KCNQ1 gene.
Disruption to the normal regulation of methylation
can give rise to altered gene expression dosage and,
FIGURE 7.26 Baby girl with Beckwith-Wiedemann syndrome.
Note the large tongue and umbilical hernia.
Patterns of Inheritance
DMR2
Centromere
Paternal allele
DMR1
ICR1
ICR2
CTCF
125
Telomere
Enhancer
CTCF
3'
5'
Other CDKN1C CTCF
genes
KCNQ1
KCNQ1OT1
IGF2 CTCF
H19
Maternal allele
FIGURE 7.27 Molecular organization (simplified) at 11p15.5: Beckwith-Wiedemann and Russell-Silver syndromes. The region contains
two imprinted domains (DMR1 and DMR2) that are regulated independently. The ICRs are differentially methylated (• methylated;
 unmethylated). CCCTC-binding factor (CTCF) binds to the unmethylated alleles of both ICRs. In DMR1, coordinated regulation
leads to expression of IGF2 only on the paternal allele and H19 expression only on the maternal allele. In DMR2, coordinated regulation leads to maternal expression of KCNQ1 and CDKN1C (plus other genes), and paternal expression of KCNQ1OT1 (a non-coding
RNA with antisense transcription to KCNQ1). Angled black arrows show the direction of the transcripts.
consequentially, features of BWS. In DMR1, gain of methylation on the maternal allele leads to loss of H19 expression and biallelic IGF2 expression (i.e., effectively two
copies of the paternal epigenotype). This occurs in up to
7% of BWS cases and is usually sporadic. In DMR2, loss of
methylation results in two copies of the paternal epigenotype and a reduction in expression of CDKN1C; this mechanism is implicated in 50% to 60% of sporadic BWS cases.
CDKN1C may be a growth inhibitory gene and mutations
have been found in 5% to 10% of cases of BWS. About 15%
of BWS cases are familial, and CDKN1C mutations are
found in about half of these. In addition to imprinting errors
in DMR1 and DMR2, other mechanisms may account for
BWS: (1) paternally derived duplications of chromosome
11p5.5 (these cases were the first to identify the BWS
locus); (2) paternal uniparental disomy for chromosome
11—invariably present in mosaic form—often associated
with neonatal hypoglycemia and hemi-hypertrophy, and
associated with the highest risk (about 25%) of embryonal
tumors, particularly Wilms tumor; and (3) maternally inherited balanced translocations involving rearrangements of
11p15.
Russell–Silver syndrome (RSS) cases are due to abnor­
malities of imprinting at the 11p.15.5 locus. Whereas
hypermethylation of DMR1 leads to upregulated IGF2
and overgrowth, hypomethylation of H19 leads to downregulated IGF2, the opposite molecular and biochemical
consequence, and these patients have features of RSS.
Interestingly, in contrast to BWS, there are no cases of RSS
with altered methylation of the more centromeric DMR2
region.
Russell–Silver Syndrome
This well-known condition has ‘opposite’ characteristics to
BWS by virtue of marked prenatal and postnatal growth
retardation. The head circumference is relatively normal,
the face rather small and triangular, giving rise to a ‘pseudohydrocephalic’ appearance (Figure 7.28), and there may
be body asymmetry. About 10% of cases appear to be
due to maternal uniparental disomy, indicating that this
chromosome is subject to imprinting. In contrast to paternally derived duplications of 11p15, which give rise to
overgrowth and BWS, maternally derived duplications
of this region are associated with growth retardation.
Recently it has been shown that about a third of
FIGURE 7.28 Girl with Russell-Silver syndrome. Note the
bossed forehead, triangular face, and ‘pseudohydrocephalic’
appearance.
126
Patterns of Inheritance
I
II
III
FIGURE 7.29 Family
inheritance.
tree
consistent
with
mitochondrial
Mitochondrial Inheritance
Each cell contains thousands of copies of mitochondrial
DNA with more being found in cells that have high energy
requirements, such as brain and muscle. Mitochondria, and
therefore their DNA, are inherited almost exclusively from
the mother through the oocyte (p. 41). Mitochondrial DNA
has a higher rate of spontaneous mutation than nuclear
DNA, and the accumulation of mutations in mitochondrial
DNA has been proposed as being responsible for some of
the somatic effects seen with aging.
In humans, cytoplasmic or mitochondrial inheritance has
been proposed as a possible explanation for the pattern
of inheritance observed in some rare disorders that affect
both males and females but are transmitted only through
females, so-called maternal or matrilineal inheritance
(Figure 7.29).
A number of rare disorders with unusual combinations
of neurological and myopathic features, sometimes
occurring in association with other conditions such as
Homoplasmy – no disease
Mild disease
cardiomyopathy and conduction defects, diabetes, or deafness, have been characterized as being due to mutations in
mitochondrial genes (p. 181). Because mitochondria have
an important role in cellular metabolism through oxidative
phosphorylation, it is not surprising that the organs most
susceptible to mitochondrial mutations are the central
nervous system, skeletal muscle and heart.
In most persons, the mitochondrial DNA from different
mitochondria is identical, or shows what is termed homoplasmy. If a mutation occurs in the mitochondrial DNA of
an individual, initially there will be two populations of mitochondrial DNA, so-called heteroplasmy. The proportion of
mitochondria with a mutation in their DNA varies between
cells and tissues, and this, together with mutational heterogeneity, is a possible explanation for the range of phenotypic
severity seen in persons affected with mitochondrial disorders (Figure 7.30).
Whilst matrilineal inheritance applies to disorders that
are directly because of mutations in mitochondrial DNA, it
is also important to be aware that mitochondrial proteins
are encoded mainly by nuclear genes. Mutations in these
genes can have a devastating impact on respiratory chain
functions within mitochondria. Examples include genes
encoding proteins within the cytochrome c (COX) system,
which follow autosomal recessive inheritance, and the G4.5
(TAZ) gene that is X-linked and causes Barth syndrome
(endocardial fibroelastosis) in males (p. 182). There is even
a mitochondrial myopathy following autosomal dominant
inheritance in which multiple mitochondrial DNA deletions
can be detected. Further space is devoted to mitochondrial
disorders in Chapter 11 (p. 181).
No disease
No disease
Severe disease
FIGURE 7.30 Progressive effects of heteroplasmy on the clinical severity of disease from mutations in the mitochondrial genome.
Low proportions of mutant mitochondria are tolerated well, but as the proportion increases different thresholds for cellular, and
hence tissue, dysfunction are breached (mauve circle represents the cell nucleus).
Patterns of Inheritance
FURTHER READING
Bateson W, Saunders ER 1902 Experimental studies in the physiology
of heredity, pp 132–134. Royal Society Reports to the Evolution
Committee, 1902
Early observations on mendelian inheritance.
Bennet RL, Steinhaus KA, Uhrich SB, et al 1995 Recommendations
for standardized human pedigree nomenclature. Am J Hum Genet
56:745–752
Goriely A, McVean GAT, Rojmyr M, et al 2003 Evidence for selective
advantage of pathogenic FGFR2 mutations in the male germ line.
Science 301:643–646
Hall JG 1988 Somatic mosaicism: observations related to clinical
genetics. Am J Hum Genet 43:355–363
Good review of findings arising from somatic mosaicism in clinical
genetics.
Hall JG 1990 Genomic imprinting: review and relevance to human
diseases. Am J Hum Genet 46:857–873
127
Extensive review of examples of imprinting in inherited diseases in
humans.
Heinig RM 2000 The monk in the garden: the lost and found genius
of Gregor Mendel. London: Houghton Mifflin
The life and work of Gregor Mendel as the history of the birth of
genetics.
Kingston HM 1994 An ABC of clinical genetics, 2nd ed. London:
British Medical Association
A simple outline primer of the basic principles of clinical
genetics.
Reik W, Surami A, eds 1997 Genomic imprinting (frontiers in molecular biology). London: IRL Press
Detailed discussion of examples and mechanisms of genomic
imprinting.
Vogel F, Motulsky AG 1996 Human genetics, 3rd ed. Berlin: Springer
This text has detailed explanations of many of the concepts in
human genetics outlined in this chapter.
ELEMENTS
1 Family studies are often necessary to determine the mode of
inheritance of a trait or disorder and to give appropriate
genetic counseling. A standard shorthand convention exists
for pedigree documentation of the family history.
2 Mendelian, or single-gene, disorders can be inherited in five
ways: autosomal dominant, autosomal recessive, X-linked
dominant, X-linked recessive, and, rarely, Y-linked inheritance.
3 Autosomal dominant alleles are manifest in the heterozygous
state and are usually transmitted from one generation to the
next but can occasionally arise as a new mutation. They
usually affect both males and females equally. Each offspring
of a parent with an autosomal dominant gene has a 1 in 2
chance of inheriting it from the affected parent. Autosomal
dominant alleles can exhibit reduced penetrance, variable
expressivity, and sex limitation.
4 Autosomal recessive disorders are manifest only in the
homozygous state and normally only affect individuals in
one generation, usually in one sibship in a family. They affect
both males and females equally. Offspring of parents who
are heterozygous for the same autosomal recessive allele have
a 1 in 4 chance of being homozygous for that allele. The less
common an autosomal recessive allele, the greater the
likelihood that the parents of a homozygote are
consanguineous.
5 X-linked recessive alleles are normally manifest only in males.
Offspring of females heterozygous for an X-linked recessive
allele have a 1 in 2 chance of inheriting the allele from their
mother. Daughters of males with an X-linked recessive allele
are obligate heterozygotes but sons cannot inherit the allele.
Rarely, females manifest an X-linked recessive trait because
they are homozygous for the allele, have a single X
chromosome, have a structural rearrangement of one of their
X chromosomes, or are heterozygous but show skewed or
non-random X-inactivation.
6 There are only a few disorders known to be inherited in an
X-linked dominant manner. In X-linked dominant disorders,
hemizygous males are usually more severely affected than
heterozygous females.
7 Unusual features in single-gene patterns of inheritance can
be explained by phenomena such as genetic heterogeneity,
mosaicism, anticipation, imprinting, uniparental disomy, and
mitochondrial inheritance.
This page intentionally left blank